This invention pertains to both a useful and novel drug-delivery device for dispensing a drug to an environment of use. Particularly, the invention pertains to a system capable of delivering a pharmaceutically active ingredient in a controlled manner, at near zero order rate. The dosage form consists of a core surrounded by an impermeable, insoluble coating, the coating having apertures which expose selected areas of the core to the environment of use. The composition of the coating is such that hydration of the core ingredients occurs only at the exposed portions of the core. The core is composed of at least two layers. One of these contains a pharmaceutically active compound. At least one other layer which does not contain a pharmaceutically active ingredient is also present. At least one polymer which swells and forms gel-like beads upon hydration is included in each layer of the core.
In the environment of use, biological fluid contacts the exposed portions of the core surface where hydration of the exposed polymer occurs. As the particles of polymer at the exposed surface absorb water, microscopic gel beads result. If the exposed portion of the core contains both a pharmaceutically active compound and microscopic gel bead forming polymer, then as the polymer swells and moves into the environment of use, the pharmaceutically active compound is carried with it. If the exposed portion of the core contains only the polymer then only the polymer moves into the environment of use.
Control of the rate of hydration of the polymer and therefore the rate of delivery of the exposed core ingredients to the environment of use is accomplished by the incorporation of holes or openings in the impermeable, insoluble coating. These holes or apertures expose discrete, predetermined sections of the core surface. Since the exposed portion of the core surface is bounded on all sides by the coating, hydration of the polymer occurs only at the pre-selected, exposed surface of the core. The resulting microscopic gel bead suspension exudes into the environment of use.
The rate of release of the pharmaceutically active ingredient is not dependent upon the solubility of the beneficial agent in the biological fluid. Rather, the release rate is essentially dependent upon the rate at which the microscopic gelatinous beads form at the exposed surface of the device and exude from the device carrying the beneficial agent and any other core excipient materials that are present. Therefore, rate of release may be controlled by controlling the size and number of holes which expose the surface of the core to the environment.
The rate of delivery of the pharmaceutically active ingredient is further dependent on the composition of the core layer exposed at the surface, at a given time. In this way, delayed delivery or intermittent delivery may be achieved by use of a core layer which does not contain the pharmaceutically active ingredient, while at the same time assuring complete delivery of the pharmaceutically active ingredient.
The need for systems that can deliver both soluble and insoluble pharmaceutically active ingredients, at a constant rate, over a four to twenty-four hour period is well established. Further, the need for a device which is capable of a programmed, delayed start of delivery is also well recognized.
Several approaches to this problem have been proposed. The existing technology relies predominantly on diffusion controlled systems which are effective only when soluble active agents are dispensed. A further limitation of osmotic systems lies in the requirement that the osmogent must dissolve in the presence of the swellable polymer any inadvertent interaction between the osmogent and the polymer can result in an unpredicted change in the rate of release of the pharmaceutically active ingredient.
Dosage forms that rely upon the establishment of an extra device superstructure have also been disclosed. However, these can be damaged during in vivo transit, for example, in the gastrointestinal tract. If portions of the superstructure break away greater surface area than desired will be exposed to the environment of use and unpredictable release of the active agent may result.
U.S. Pat. No. 4,814,182 discloses the use of rods or slabs of pre-hydrated and swelled polyethylene oxide hydrogel. The polymer is impregnated with a biologically active agent during a hydration procedure. The hydrated polymer is then dried and partially coated with an impermeable, insoluble material. When placed in an aqueous environment, the polymer swells but does not dissolve or disintegrate. The entrapped active ingredient is released from the polymer by diffusion. The mechanism of release is based on the ability of the soluble drug to diffuse through the rehydrated hydrogel and move into the aqueous environment.
U.S. Pat. No. 4,839,177 discloses the use of hydrogels compressed to defined geometric forms that are admixed with biologically active ingredients where a portion of the device is affixed to a "support platform" made of an insoluble polymeric material. When hydrated, the swellable, gellable hydrogel expands beyond the device and establishes a superstructure from which the active agent is released either by diffusion, if the active agent is soluble, or by erosion, if the active agent is insoluble. The generation and maintenance of the superstructure is vital to the success of this device.
An osmotic dosage form which utilizes a semipermeable wall containing at least one "exit means" which passes through the wall, surrounding a core containing an osmotic agent, a neutral and ionizable hydrogel and an active ingredient is disclosed in U.S. Pat. No. 4,971,790. The coating of this device is permeable to water from the environment of use. Water moves into the core through the semipermeable membrane. Once inside the device, the water solubilizes the osmotic agent and ionizable hydrogel. Pressure builds up inside the device, due to the ionization of the osmogent. Ultimately, the solubilized, ionizable hydrogel, containing the beneficial agent, the neutral hydrogel and other core excipients are pumped out of the core, through an exit means and into the environment of use.
U.S. Pat. No. 4,915,954 discloses a device having a two layer core. One layer is faster releasing than the other and is primarily composed of a mixture of hydroxypropyl cellulose and hydroxypropylmethyl cellulose. The lower layer can also be made up of cellulosic polymers but of different or higher molecular weight. This slower layer may also contain a hydrogel, preferably polyethylene oxide. This device requires a semipermeable wall. The need to control wall thickness (or weight of wall) and its effect on permeability and subsequently on release is shown in example 4 and FIG. 7 of the disclosure. Control of wall thickness is one of the major negative features of osmotically controlled delivery devices.
European Application 0 378 404 A2 discloses a microporous coating on a hydrogel osmotic core. This device comprises a coating through which the pharmaceutically active agent may pass when the device is exposed to an aqueous environment. Like the other devices discussed, wetting, hydration or solubilization of the core material by the inhibition of fluid through the coating must occur for this device to function.
U.S. Pat. No. 5,366,738 discloses a device which consists essentially of a homogeneous compressed core prepared from an admixture comprising a therapeutically effective amount, of a pharmaceutically active ingredient and a polymer, which forms microscopic gelatinous beads upon hydration. This core is coated with a water insoluble, water impermeable polymeric coating, which surrounds and adheres to the core, the coating having a plurality of apertures, exposing between about 5 and about 75% of the core surface. While this dosage forms provides a means for controlling release of an insoluble pharmaceutically active ingredient, delayed delivery is not provided.
The usefulness of the above devices would be increased if a device and method were provided to improve the release of pharmaceutically active ingredients, at a constant rate, and if a means for delaying release of the pharmaceutically active ingredient was also possible. Further improvement would be realized if a dosage form was provided that provides for intermittent delivery of the pharmaceutically active ingredient.